There are many steps in the biosynthesis and utilization by the tissues of testosterone. Testosterone is made mostly in the testicles. A lesser amount is made in the adrenals. Production is stimulated by secretion of GnRH or LHRH by the brain, which causes secretion of luteinizing hormone (LH) by the pituitary, which causes the testicles to make testosterone. Testosterone then flows into the blood stream and is absorbed by the target cells. Here it binds to a receptor and is transported into the cell and converted to dihydrotestosterone. This is bound and carried to the nucleus of the cell where it redirects cellular activity by turning on and off DNA. Hormonal manipulation is a term which refers to the reduction of testosterone or its effects by blocking any step in the above process in order to gain a desired effect. Until now the uses of hormonal manipulation include for example treating prostatic carcinoma, and treatment for baldness.
The present invention involves the use of hormonal manipulations in the prevention and treatment of atherosclerosis, including coronary heart disease, stroke, and peripheral vascular disease, We have already discovered as reflected by our patents that certain 5-alpha reductase inhibitors (finasteride) are effective (#U.S. Pat. No. 6,090,409) for treating and preventing atherosclerosis and its complications, including coronary artery heart disease. Several LHRH agonists; Leuprolide (U.S. Pat. No. 6,099,851) and Goserelin.(U.S. Pat. No. 6,140,315), which inhibit testosterone metabolism at another step have also shown to be effective.
For instance, leuprolide acetate is one of the compounds we previously discovered being effective in the prevention of such cardiac events. Leuprolide acetate is a synthetic nonapeptide of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH), the chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate salt sold under the trade name Lupron or Lupron Depot, as identified by U.S. Pat. No. 4,897,256, the entire disclosure in incorporated by reference herein, is known for use in the treatment of prostatic carcinoma. Leuprolide is known to decrease levels of LHRH, LH and Testosterone (a sex hormone).
Another compound we previously discovered as being effective in the prevention of such cardiac events is Goserelin acetate. Goserelin Acetate is a synthetic decapeptide analogue of LHRH or GnRH, is chemically described as an acetate salt of [D-Ser(Bu.sup.t).sup.6 Azygly.sup.10] LHRH. Its chemical structure is pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu.sup.t)-Leu-Arg-Pro-Azgly-NH2 acetate [C59H84N18014 (C2H4O2) sold under the trademark Zoladex, as identified by the U.S. Pat. No. 5,510,460, the entire disclosure is incorporated by reference herein, is known for the use in treatment of prostatic carcinoma. Goserelin acetate is known to reduce levels of GnRH or LHRH, and Testosterone, a sex hormone.
Finasteride, a synthetic 4-azasteroid compound. 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-(5a 17B)-, sold under the trade name Proscar by Merck and Co., as identified by U.S. Pat. No. 5,175,155, the entire disclosure is incorporated by reference herein, is known for use in treatment of benign prostatic hypertrophy (BPH). Finasteride is known to inhibit testosterone metabolism by blocking conversion of testosterone to dihydrotestosterone by blocking 5-alpha-reductase. Finasteride is yet another compound we previously discovered as being effective in the prevention of cardiac events.